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Clinical Cancer Research 13, 4123, July 15, 2007. doi: 10.1158/1078-0432.CCR-07-0609
© 2007 American Association for Cancer Research
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Imaging, Diagnosis, Prognosis

MDM2 SNP309 Polymorphism as Risk Factor for Susceptibility and Poor Prognosis in Renal Cell Carcinoma

Hiroshi Hirata1, Yuji Hinoda2, Nobuyuki Kikuno1, Ken Kawamoto1, Yutaka Suehiro2, Yuichiro Tanaka1 and Rajvir Dahiya1

Authors' Affiliations: 1 Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California and 2 Department of Laboratory Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan

Requests for reprints: Rajvir Dahiya, Urology Research Center (112F), Veterans Affairs Medical Center and University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121. Phone: 415-750-6964; Fax: 415-750-6639; E-mail: rdahiya{at}urol.ucsf.edu.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism in the MDM2 promoter region SNP309 (rs2279744) has been shown to increase the affinity of the transcriptional activator Sp1, resulting in elevated MDM2 transcription and expression in some cancers. There is currently no information about the role of MDM2 polymorphism in renal cell carcinoma (RCC). We investigated polymorphisms in p53-related genes, including MDM2, and their interactions in renal cancer.

Experimental Design: We genotyped three single nucleotide polymorphisms of three genes (p53 Arg72Pro, p21 Ser31Arg, and MDM2 SNP309) in 200 patients with renal cancer and 200 age- and gender-matched healthy subjects. Genotyping was confirmed by direct DNA sequencing. Samples that showed significant polymorphic variants were analyzed for MDM2 expression by immunohistochemistry. Association of polymorphic variants on survival of RCC patients was analyzed by Kaplan-Meier curves.

Results: A significant increase in the GG genotype of the MDM2 SNP309 was observed in RCC patients compared with healthy controls (odds ratio, 1.80; 95% confidence interval, 1.14-2.84). To investigate the effect of the MDM2 SNP309 polymorphism on MDM2 expression, immunohistochemistry was done in genotyped RCC tissues. Positive staining for MDM2 was detected in 2 of 15 (13%) TT genotype, 4 of 15 (26%) TG genotype, and 5 of 10 (50%) GG genotype carriers. The frequency of MDM2 expression in GG genotype carriers was significantly higher than that in TT genotype carriers. Polymorphisms of p53 Arg72Pro and p21 Ser31Arg did not show significant association with RCC. In univariate and multivariate analysis, MDM2 SNP309 GG genotype was independently associated with poor prognosis. Kaplan-Meier curve analysis showed that survival of patients with GG carriers was significantly worse than that of carriers with TG + TT genotypes.

Conclusions: This is the first report to show a significant association between functional polymorphisms in MDM2 and increased risk of developing renal cancer. In addition, the MDM2 polymorphism was shown to be an independent adverse prognostic factor for RCC. Patients with MDM2 309GG genotype showed worse prognosis and low survival.

Renal cell carcinoma (RCC) is the third leading cause of death among urological tumors, accounting for ~2% of adult malignancies (1). Although the rate of detection of incidental RCC has increased with improved diagnostic techniques, metastatic lesions are still found at diagnosis in ~25% of RCC patients. Etiologic studies of familial and sporadic RCC have shown that the von Hippel-Lindau tumor suppressor gene, located on chromosome 3p25-26, is associated with RCC. Mutation of the von Hippel-Lindau gene causes familial von Hippel-Lindau disease, and the loss of two von Hippel-Lindau alleles has been observed in the vast majority of sporadic RCC (2, 3). Epidemiologic studies have suggested that gender, obesity, smoking, analgesic, diuretic abuse, and environmental factors are associated with RCC (4, 5).

p53 is a tumor suppressor gene that initiates apoptosis in response to severe DNA damage (6). p21 (CDKN1A, Waf1) is a cell cycle checkpoint gene functioning as downstream effectors of p53 and acts as an inhibitor of cyclin-dependent kinase (7). In response to DNA damage, cell cycle arrest at the G1 to S phase is caused by p21 through p53 up-regulation (6). MDM2 is a crucial negative regulator of p53 through several mechanisms. MDM2 directly binds to p53, resulting in the inhibition of p53 transactivation activity (8–10). MDM2 also acts as an ubiquitin protein ligase and controls p53 by targeting it for proteasomal degradation (8–10). Therefore, overexpression of MDM2 leads to the increased degradation of p53 and down-regulates its tumor suppressor function.

In this study, we focused on possible functional polymorphisms in p53, p21, and MDM2, although each gene has many polymorphic sites. There is a common nonsynonymous single nucleotide polymorphism (SNP) at codon72 of p53 (Pro72Arg, rs1042522), which has been studied in many cancers (11–13). In an in vitro study, the p53 Arg/Arg genotype induced apoptosis more efficiently than the Pro/Pro genotype (14). It has been reported that the frequency of the Pro/Pro genotype is higher in various cancer patients compared with controls (11–13) and this genotype may be linked to decreased function of p53. About p21, a nonsynonymous polymorphism of Ser31Arg (rs1801270) was shown to be associated with increased risk of head and neck and prostate cancer (15, 16). In an in vivo study, Su et al. (17) showed that the Ser31Arg of p21 was associated with a significant decrease in p21 mRNA expression in the peripheral leukocytes with lung cancer. The MDM2 SNP309 (rs2279744) has also been shown to have a functional role. This polymorphism is localized in an intronic promoter region of MDM2 and binds stimulatory protein (Sp1) with increased affinity (18). It was revealed that cells carrying the 309GG genotype had increased MDM2 mRNA and protein expression (18). In addition, there have been several reports suggesting the association of this SNP with various cancers (11, 19–21) and the correlation between MDM2 expression and poor prognosis (21).

The importance of p53 inactivation in RCC remains controversial, although a few studies have suggested that p53 and MDM2 up-regulation are independent predictors of poor survival (22, 23). Haitel at al. (22) did immunohistochemistry for both p53 and MDM2 in RCC and found that MDM2/p53 co-overexpression is a poor survival predictor. Recently, Weiss et al. (24) showed a relationship between p21 expression and prognosis. The relationship of p53 Arg72Pro, p21 Ser31Arg, or MDM2 SNP309 with cancer susceptibility has been evaluated for several cancers (19–21, 25–29), but no reports have been published about RCC. In this study, we therefore examined the relationship of RCC with p53, p21, and MDM2 polymorphisms.


   Materials and Methods
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Samples. A total of 200 patients (140 male and 60 female) with pathologically confirmed conventional RCC and 200 age- and sex-matched control individuals was enrolled in this study. The mean ages of the patient and control groups were 64 years (range, 29-87) and 63 years (range, 32-89), respectively (P = 0.44; Table 1 ).


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  		Table 1. Characteristics of RCC patients and controls

 
To adjust for age, the number of subjects in two age groups was matched between cases and controls (P = 1.0; Table 1). All of the patients tested were diagnosed with RCC based on histopathologic findings. They were classified according to the WHO criteria and staged according to the tumor-node-metastasis classification. Healthy controls consisted of volunteers with no apparent abnormal findings on medical examination at Shimane University Hospital. Peripheral blood samples were obtained from the patients and controls after written informed consent was obtained. All patients and healthy controls were native Japanese and resided in Shimane prefecture or adjacent prefectures. Peripheral blood samples were obtained from the patients and controls after written informed consent was obtained.

The participation rate was 95% and 80% for the patients and controls, respectively. There were no significant differences between patients and control groups with regard to family history of cancer and body mass index.

Genotyping. The polymorphisms were analyzed by PCR-restriction fragment length polymorphism (RFLP) and single-strand conformational polymorphism (SSCP). Genotyping methods, primer sets, and annealing temperatures used for the RFLP and SSCP are shown in Table 2 (27, 28). Each PCR was carried out in a total volume of 20 µL consisting of 0.3 µL of a 10 µmol/L solution of each primer, 1.5 mmol/L MgCl2, 0.8 mmol/L deoxynucleotide triphosphate, 0.5 unit REDTaq DNA polymerase (Sigma), 1 µL of genomic DNA (80 ng/µL), and 15.7 µL H2O using a PTC 200 Thermal Cycler (MJ Research). The PCR program had an initial denaturation step of 7 min at 94°C followed by 35 cycles of 30 s at 94°C, 45 s of annealing at 57°C, and 45 s at 72°C. For RFLP analysis, PCR products were digested with BstUI, MspA1I, and BlpI (New England Biolabs) for p53 codon72, MDM2 SNP309, and p21 codon31, respectively, by the manufacturers' protocols. The PCR products were separated by electrophoresis in a 2% agarose gel and subsequently stained with ethidium bromide. SSCP was done using the following nonradioactive method. Briefly, a mixture of 5 µL PCR product and 7 µL SSCP loading dye [composed of 950 µL formamide, 40 µL of 0.5 mol/L EDTA (pH 8.0), and 4 µL of 0.05% bromphenol blue] was used. The mixture was placed on ice immediately after denaturation at 97°C for 5 min. The mixture (5 µL) was loaded onto 12% polyacrylamide gels and electrophoresis was done at 4°C for 10 h at 30 W with Tris-glycine as running buffer. Gels were stained with a 1:10,000 solution of GelStar (Cambrex Bio Science Rockland) in Tris-glycine buffer for 10 min with stirring at room temperature and examined using an UV transilluminator. To confirm the genotype ascribed by RFLP and SSCP, the PCR products were subjected to direct sequencing.


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  		Table 2. Genotyping, primer sequences, length of PCR products, and restriction enzymes

 
Immunohistochemistry study. Immunostaining of MDM2 was done in formalin-fixed, paraffin-embedded specimens using a mouse monoclonal antibody against human MDM2 (Santa Cruz Biotechnology). The staining procedure was according to a commercial kit (Santa Cruz Biotechnology). The sections were counterstained with Harris' hematoxylin. A pathologist, not involved in the present study, evaluated the immunostaining under blind conditions. Immunohistochemical staining was graded on an arbitrary scale from 0 to 2+; 0 representing negative expression (0-25% positive cells), 1+ representing weakly positive expression (25-50% positive cells), and 2+ representing strongly positive expression (50-100% positive cells). The scale was determined according to the average rate of positive cells in 10 random fields of all slides.

Statistical analysis. Hardy-Weinberg equilibrium was evaluated using SNPAlyze version 2.2 (DYNACOM Co. Ltd.). The {chi}2 test was used to compare the genotype frequency between patients and controls. The odds ratio (OR) was obtained by unconditional logistic regression analysis and adjusted for age and gender as a continuous variable. All statistical analyses were done using StatView (version 5; SAS Institute, Inc.). A P value of <0.05 was regarded as statistically significant.


   Results
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 Materials and Methods
 Results
Discussion
 References
 
Characteristics of RCC patients and controls. Table 1 depicts the mean age, gender, tumor grade, and pathology of individual RCC patients. Two-tailed Student's t tests were used to compare the distributions of age and gender between patients and control subjects. In the 200 RCC cases, 144 (72%) were localized and 170 (85%) were grade 1 and 2.

Hardy-Weinberg equilibrium. The genotype frequencies of the four polymorphisms in total samples (n = 400), RCC patients (n = 200), and healthy controls (n = 200) were consistent with the Hardy-Weinberg equilibrium distribution (P > 0.05).

p53, MDM2, and p21 polymorphism and RCC. The genotype distributions of the p53 codon72, MDM2 SNP309, and p21 codon31 polymorphisms between the RCC cases and healthy controls are shown in Table 3 . The frequencies of the variant alleles between cases and controls were as follows: p53 codon72 (0.39, 0.39), MDM2 SNP309 (0.53, 0.45), and p21 codon31 (0.56, 0.56). A significant increase in the GG genotype of the MDM2 SNP309 polymorphism was observed in patients compared with controls (OR, 1.80; 95% confidence interval (95% CI), 1.14-2.84; P = 0.012; Table 3). As the median age was 64 years, we divided the case and control groups at that age and compared the genotype frequencies between the two groups. The increased risk was evident among those subjects who were under 65 years old and had the two G alleles (OR, 3.00; 95% CI, 1.42-6.71; Table 4A ). We also examined the combined effect of the p53 codon72 Arg/Pro and the other genes. However, there is no additional effect from the p53 Arg72Pro polymorphism when the risk of combined genotypes was analyzed (Table 4B).


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  		Table 3. p53, MDM2, and p21 gene genotypes and renal cancer risk

 

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  		Table 4. The association of an early age of RCC onset with MDM2 SNP309 and combined effect of p53

 
Comparison MDM2 expression according to MDM2 SNP309 genotyping. To investigate the effect of the MDM2 SNP309 polymorphism on MDM2 expression, immunohistochemistry was done in some of the genotyped RCC tissues. Positive staining for MDM2 was detected in 2 of 15 (13%) TT genotype, 4 of 15 (26%) TG genotype, and 5 of 10 (50%) GG genotype carriers. The frequency of MDM2 expression in GG genotype carriers was significantly higher than that in TT genotype carriers (P = 0.04; Fig. 1 ).


Figure 1
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  		Fig. 1. Effect of MDM2 genotype on MDM2 expression. Tumors were scored as follows: score 0, no appreciable staining or staining in <25% of cancer cells; score 1+, tumors with weak appreciable incomplete nuclear and cytoplasmic staining in 25% to 50% of cancer cells; score 2+, strong immunoreactivity of the nucleus and cytoplasm in >50% of cancer cells. Tumors classified as 0 were considered "negative," and those scored as 1 or 2 were classified as "positive." IHC, immunohistochemistry. **, positive staining: (1+2) /(0+1+2) x 100(%)

 
Univariate and multivariate Cox proportional hazard analysis for cancer-specific survival in RCC patients. The prognostic value for tumor-related survival of the variables, including gender, age at diagnosis, tumor grade, pathologic tumor-node-metastasis, and SNPs (MDM2 SNP309, p53 codon72, p21 codon31), was analyzed using Cox proportional hazards analysis (Table 6). In the univariate analysis, tumor grade, pT, pN, pM, and MDM2 SNP309 were associated with survival (Table 6; Fig. 2 ). In the multivariate analysis, pT, pN, and pM had the same result. The hazard ratio for MDM2 SNP309 was 1.92 (0.94-3.86), showing a borderline significance as an independent risk factor for survival.


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  		Table 6. Univariate and multivariate Cox proportional hazard analysis for prognosis in RCC patients

 

Figure 2
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  		Fig. 2. Cancer-specific survival based on Kaplan-Meier curves for 176 RCC patients. A, MDM2 SNP309 GG is an independent predictor of cancer-specific survival (P = 0.0139). Survival of GG carriers was statistically significantly worse than that of carriers with TG + TT genotypes. B to D, pT3/pT4, pN1/pN2, and pM1 are independent predictors of cancer-specific survival (P < 0.0001).

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this study, we showed that the MDM2 SNP309 polymorphism is associated with an increased risk of renal cancer. Moreover, we used immunohistochemistry to investigate MDM2 expression in renal cancer tissues from different genotype carriers because there have been no reports about the relationship between the MDM2 SNP309 polymorphism and expression of MDM2 in RCC. This is a first report documenting that the MDM2 GG genotype carriers have significantly higher MDM2 expression in renal cancer tissues compared with TT or TG genotype carriers (Table 5 ). Haitel et al. (22) investigated MDM2 expression in renal cancer tissues immunohistochemically and showed that overexpression of the MDM2 is an independent predictor for poor survival.


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  		Table 5. Effect of MDM2 SNP309 polymorphism on MDM2 expression

 
Among other cancers, there is a significant correlation between MDM2 expression and poor prognosis (30). We investigated whether MDM2 SNP309 polymorphism is a predictive variable in RCC. In the univariate analysis, tumor grade, tumor-node-metastasis, and the MDM2 SNP were statistically significant as prognostic factors. In addition, multivariate Cox proportional hazard analysis revealed that this polymorphism could be an independent prognostic factor (Table 6 ; Fig. 2). Among gastric and esophageal cancer patients, MDM2 GG carriers were shown to be significantly associated with poor survival (20, 21). Our present results agree with those findings. Therefore, the MDM2 SNP309 polymorphism may provide important prognostic information about survival in renal cancer.

The p21 is one of major effectors of p53 and negatively controls cell proliferation by inhibiting several cyclin-dependent kinase complexes. In response to DNA damage, p53 up-regulates p21, resulting in G1 phase cell cycle arrest. The loss of p53 function leads to the attenuation of p21 expression, although the p53-independent pathway also regulates p21 expression (31). Although p21 mutation is rare in RCC cell lines (32), SNPs of p21 are thought to change its function and the p21 codon31 SNP has been reported to be associated with several cancers (27). However, in this study, the p21 codon31 polymorphism was not significantly associated with risk for RCC (Table 3).

The p53 pathway is an important response to oncogenic stress, and p53 regulates its own intracellular levels through an autoregulatory feedback pathway with MDM2 (30). MDM2 binds to p53 and inactivates it through ubiquitination. MDM2 is a proto-oncogene and loss of p53 function is caused by MDM2 overexpression, mutations, and other mechanisms, resulting in malignant transformation or carcinogenesis (33, 34). In the p53 pathway, p53, p21, and MDM2 play a crucial role together. Polymorphisms in p53-MDM2 (19, 20, 25, 29) and p53-p21 (26, 27) have been reported to be associated with other cancers, such as lung, esophageal, colorectal, breast, and gastric cancer. Based on this evidence, we investigated whether these gene polymorphisms and their gene-gene interaction may be important in RCC. In this case-control study for each polymorphism, a significant association with renal cancer was observed only for the MDM2 SNP309, although additional polymorphisms in the other genes have been linked to susceptibility for other cancers (20, 26, 27, 29).

We found that there was no additional effect from the p53 Arg72Pro polymorphism when the risk of combined genotypes was analyzed because the OR was the same as the one from the MDM2 TT/TG compared with the GG genotype. The p53 polymorphism did not have any effect on cancer-specific survival in univariate analysis (Table 6). Bond et al. (18) have shown the SNP of MDM2 309GG to be associated with age at diagnosis. We compared the average age at diagnosis with SNP309 genotype and found no difference between the three genotypes (TT, TG, and GG; data not shown). We also found that there was an increased risk of RCC in those under 65 years old (Table 4A). This significant association may be due to different distribution of genotypes among controls, not from cases.

Therefore, the MDM2 SNP309 GG genotype may be important in early onset of RCC.

In conclusion, this is the first report to show a significant association between a functional polymorphism in MDM2 and increased risk of developing renal cancer. Moreover, the patients with MDM2 309GG genotype showed worse prognosis and low survival.


   Acknowledgments
 
We thank Dr. Roger Erickson for his support and assistance with the preparation of the manuscript.


   Footnotes
 
Grant support: NIH grants RO1CA101844, RO1AG21418, R01CA111470, R01CA108612, and T32-DK07790; Veterans Affairs Research Enhancement Award Program award; Merit Review grants; and Yamada Science Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/14/07; revised 5/ 2/07; accepted 5/ 7/07.


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